The goal of this project is to determine the mechanism by which normal T4 lymphocytes from certain individuals are resistance to infection by certain HIV-I isolates. This phenomenon we conclusively demonstrated in a recent study, which showed that T4 lymphocyte resistance was polymorphic among donors of PBLs. Three donors of 12 tested possessed T4 lymphocytes resistant to 1 out of 10 different HIV-1 isolates each (two donors resistant to HIVC and one donor resistant to HIVAC1). Once the mechanism of this resistance is known, we will be able to make judgements concerning the feasibility of exploiting it as a general therapy against HIV. Thus, our aims are to: 1) determine which step(s) in infection/replication of HIV is blocked in T4 lymphocytes from resistant donors, 2) determine the genetic nature of this resistance by following segregation of the resistance phenotype among family members of resistant donors, 3) attempt to identify and/or map that host gene(s) involved by molecular cloning and linkage analysis, and 4) determine the host cell molecules or processes conferring this resistance. The significance of this work relates both to understanding variable disease outcomes of HIV infection in different people and to a potential for a new avenue for rational drug design.